5-cyano and 5-carbamyl steroid derivatives



rates" 3,050,518 S-CYANO AND S-CARBAMYL STERGID DERIVATHVES Albert Bowers and Howard J. Ringold, Mexico City, Men ico, assignors, by niesne assignments, to Syntex Corps ration, a corporation of Panama No Drawing. Filed Inly 17, 195%, Ser. No. 827,679 Claims priority, application Mexico Ziniy 22, 1958 2d Claims. (Qt. 26ti239.55)

This invention relates to certain new cyclopentanophenanthrene derivatives and to a process for their preparation.

More particularly, it relates to the novel S-cyano and S-carbamyl analogs of the 4,5-dihydro derivatives of steroidal M-hormones.

The new compounds which are the object of the present invention exhibit valuable therapeutic properties: they are antiestrogenic agents and show anti-pituitary activity.

These new anti-estrogenic agents and anti-pituitary agents are 5-cyan0 and S-carbamyl analogs having the general formula:

wherein A is a radical arrangement selected from the group consisting of H lower aliphatic radical, lower aliphatic radical, i OH 0 H acyloxy H H acyloxy a 2' 00.0Ha CO.CH2OH CO.CHa

bis-methylenedioxy(Bl /iD), and

O0.0HzOH while R is a member selected from the group consisting of hydrogen and methyl; X is a member selected from the group consisting of hydrogen and fluorine; Y is a member of the group consisting of Patented Aug. 21, 1962 The process according to the invention for preparing S-cyano and S-carbamyl analogs of the 4,5 derivatives of steroidal A -3-keto hormones essentially consists in the reaction of such hormones with the cyanide of an alkali or alkaline earth metal, in the presence of a hydroxylated organic solvent.

The starting compounds for carrying out this process can be characterized by the following general formula:

A R 1 j 42 wherein A, R, X and Y have the same meaning as in the preceding formula.

The process of the invention can be represented by the following equation:

A, R, R, X and Y having the same meaning as explained hereinbefore.

More specifically, as starting material for the process according to our invention there can be used: testosterone, A -androsten-3,17-dione, a 17a-alky1 (alkenyl, alkinyl)- testosterone or its esters, progesterone, desoxycorticosterone, a 17a-acyloxy-progesterone, as well as the 19-noranalogs of such compounds, all of which may optionally be oxygenated at C-l1 with a ,B-hydroxyl or a keto group 'and/ or fluorinated at C-t Formula I also represents the 17 ,20;2(),21 bis methylenedioxy derivatives of Reichsteins Compound S, of 19-nor-S and of their analogs oxygenated at (3-11 and/ or fluorinated at C-9u (cf. Sarett et al., J. Am. Chem. Soc., 80, 1517 (1958)).

The process of the invention comprises the step of reacting one of the above-mentioned starting compounds with potassium cyanide. Preferably, the starting com pound is refluxed with potassium cyanide in mixture with ethanol for a period of 1-5 hours and there is obtained a mixture of the 5d. and 5,8 isomers of the S-cyano' and S-carbamyl analogs of the 4,5-dihydro derivatives of the respective A -3-keto hormones, and the mixture is separated into its components by chromatography.

Instead of potassium cyanide, there can be used another alkali metal cyanide such as sodium cyanide or calcium cyanide. Instead of ethanol, other hydroxylated organic solvents such as, for instance, a butanol, may be used.

More particularly, if the starting compound is testosterone, there are obtained the 5ozand S ft-isomers of S-cyanoandrostan-17p-ol-3-one and of S-carbamyl-androstan- 17fi-ol-3-one.

Progesterone yields the 5aand Sit-isomers of S-cyanopregnan-3,20-dione and of 5-carbamyl-pregnan-3,ZO-dione;

and desoxycorticosterone aifords the Sotand Sfi-isomers of S-cyan'o-pregnan-Zl-ol-3,20-dione and of 5-carbarnylpregnan-21-ol-3,20-dione.

A testosterone substituted at C-17a with the residue of a lower aliphatic hydrocarbon, saturated or unsaturated, used as the starting compound lafiords the 506- and 55- isomers of the respective 17a-alkyl(alkenyl or alkinyl)- S-cyano-androstan-175-ol-3-one and of the corresponding 17aall yl(a1kenyl or alkinyl)-5-carbamyl-androstan-17,8- ol-3-one.

A 17-ester of one of the last mentioned testosterone derivatives used as the starting compound yields the corresponding S-cyano and S-carbamyl compounds esterified at -17, and a 17-ester of 17a-hydroxy-progesterone permits to obtain the 511- land SB-isomers of the corresponding 17-ester of -cyanoapregnan-l7a-ol-3,ZO-dione and of S-carbamyl-pregnan-17u-ol-3,20-dione.

In the compounds of Formula II having a primary hydroxyl group at 0-21 or a secondary hydroxyl group at 0-175, these groups can be esterified by reaction with the anhydride of a hydrocarbon carboxylic acid of up to 12 carbon atoms, in pyridine solution; the anhydride may be derived from a hydrocarbon carboxylic acid of up to 12 carbon atoms, saturated or unsaturated, of straight, branched, cyclic or mixed cyclic-aliphatic chain, with or without methoxy, halogen or other substituents in the chain. We prepared among others, such esters as the acetates, propionates, butyrates, t-butyrates, hemisuccinates, enanthates, caproates, benzoates, trimethylacetates, phenylpropionates, phenoxyacetates, cyclopentylpropiomates and fl-chloropropionates; the starting compounds (I) may possess similar ester groupsand, therefore, the reaction products obtained from the cyanide treatment according to the invention are correspondingly esterified.

From the bis-methylenedioxy (BMD) derivatives there were obtained the BMD derivatives, wherein the dihydroxyacetone side chain was regenerated by treatment with an aqueous organic acid. Thus, if the starting compound is 17,20;20,21-bis-methylenedioxy-A -pregnen-3- one, there are obtained the 50cand Sit-isomers of 5- cyano 17,20;20,21 bis methylenedioxy pregnan 3- one and of 5-carbamyl-17,20;20,2Ibis-methylenedioxypregnan-3-one.

Starting compounds which have at 0-10 a hydrogen atom instead of the angular methyl group, yield the 5- cyano and 5-carbamyl derivatives of the 19-nor-analogs of the above mentioned compounds.

In accordance with a further feature of the process according to the invention, the starting compounds are oxygenated at 0-11 with a fl-hydroxyl or keto group, or oxygenated at 0-11 and fluorinated at C-90t, to produce the final compounds of the type described above correspondingly substituted at (3-11 or at C-11 and C-9.

The above-mentioned 17,20;20,21-bis-methylenedioxy compounds and their 19-nor analogs or' ll-oxygenated or 9ot-fluorinated derivatives are treated with an aqueous organic acid in order to regenerate the dihydroxyacetone side chain, for example by heating with aqueous formic acid; there are thus treated the bis-methylenedioxy derivatives of the 50C- and SIS-isomers of 5-cyano-pregnan-17a, 21-diol-3,20-d.ione and of the corresponding compounds of the 19-nor-series, as well as those having an oxygen function at 0-11 or an oxygen function at 'C11 and a fluorine atom at C-9a; there are obtained the respective S-cyano and S-carbamyl analogs of pregnan-17a,21-diol- 3,20-dione with or without the angular methyl group at 0-10 and/or with an oxygen function at C 11 or an oxygen function at C-ll and a fluorine atom at (1-904.

According to another variation in practicing the process of invention, the 17,20;20,21-bis-rnethylenedioxy compounds are treated with aqueous acetic acid in the hot and the products resulting from this reaction are acetylated at 0-21 by treatment with acetic anhydride in pyridine solution. There are thus obtained the above mentioned final compounds in the form of their 21-acetates.

The following specific examples serve to illustrate but are not intended to limit the present invention.

EXAMPLE I A mixture of 5 g. of testosterone, 8 g. of potassium cyanide and 200 cc. of ethanol was refluxed for 3 hours, cooled diluted with water and extracted with ether. The extract was washed with water, dried over anhydrous sodium sulfate and evaporated to dryness.

were isolated.

results.

EXAMPLE II In another experiment, in accordance with the preceding example, methanol was substituted for ethanol, and the mixture was refluxed for 5 hours, with the same final Following the procedures of the previous examples, the final products listed in Table I given hereinafter can be obtained from the indicated starting materials:

Table l ExlaImple Starting Compound Products III 19-nor-testosterone 5a and fits-isomers of 5-cyano-l9- nor-androstan-l7flp1-8-one and 5-oarbamyl 19 nor-androstan- 17 3-ol-3-one.

IV ll-keto-testosterone-- 5n: and fifi-isomers of 5-cyanoandrostan 17B ol-3,11 dione and 5-carbamyl-androstan-Nfi- 0l-3,l1-dione.

V llfl-hydroxy- 5a and 5B-isorners of 5-cyanotestosterone. androstan 115,176 diol 3- one and 5-carbamyl-androstan-llfl 17fi-diol-3-0ne. VI 11 keto 19 nor testos- 5a and 5,8-isomers of fi-oyanoterone. 19 nor androstan 17B o1 3,

ll-dione and of fi-earbamyl-IQ- nor androstan 17B ol 3, ll-djone. VII 113 hydroxy 19 nor- 5a and 5fl-isomers of 5-cyauotestosterone. 19 nor androstan-11fl,17fl-diol- 3-one and of 5-earbamyl-19-norandrostan-llfi,l7B-diol-3-one. VIII 17aacetoxyprogester- 50 and fifi-isomers of 5-cyanoone. 17a-acetoxy-pregnan-3,20 dlone and of fi-carbamyl-Haacetoxy pregnan-3,20-dione.

IX ll-clesoxycorticosterone.. 5a and 5,8-isomers of 5-eyanopregnan 21 ol 3,20-dione and 5-earbam Lprcgnau-21 o l-3,20- dione.

X Gortlcosterone 5a and fifl-isomers of 5-eyan0- pregnau-11B,21-diol 3,20 dione and 5-carbamyl-pregnan-lll9, 2l-diol-3,20-dione.

XI A pregnen 21 01-3, 5a and 5fl-isomers of 5-cya110- 11,20-trione. pregnan 21 ol 3,11,20 trione and 5-oarbarnyl-pregnan-2l-ol- 3,11,20-trione.

XII 19-1101' 11 desoxycor- 5c: and 5fl-isomers of fi-cyanotlcosterone. l9-nor-pregnan-2l-ol-3,20 dione and 5-carbarnyl-19-nor-pregnan- 21-o1-3,20-dione. V

XIII 19-nor-corticosterone. 5a and 5fl-isomers .of 5-cyano- 19 nor pregnan- 115,21 diol-H, 20-dione and 5-carbamyl-19- nor pregnan 115,21 diol 3,20- dione.

XIV 19-norA -pregnen 21 5a: and 5B-is0mers of 5-cyanool-3,11,20-trione. lll-norpregnan 21 ol 3,11,20- trione and 5-earbamyl-l9-norpregnan 21 0l 3,11,20 trione.

XV 17,20;20,21 bis meth- 5a and 5B-isomers of 5-eyanoylenedioxy pregnan- 17,20;20,21 bis methylene- 3-one. dioxy-pregnan-3-one and 5- oarbamyl 17,20;20,21 bismethylenedioxy-pregnan-iione. XVI IQ-nor-analog of starting l9-nor analog of products of 2cgrupound of Example Example XV.

XVII 11f] hydroxy analog of llfl-hydroxy-analogs of products starting compound of of Example XV. Example XV.

XVIII ll-keto-analog of starting ll-keto-analogs of products of compound of Example Example XV. XV (17,20;20,2l- B MID-cortisone).

XIX 9a-fluoro analog of start- .lcr-fluoro analogs of products of ing material of Exam- Example I. ple XV.

Table I-Cont1nued Table III Exlalmple Starting Compound Products ExlaImple Starting Material Acid Anhydride Final Product 5 XX l7a-propyl-testosterone 5a and 5,8-iso1ners of the 5-cyano- XXXIII. 5a-cyano prodacetic anhy- 17-acetate of 5a-Cyand B-carbamyl analogs of 17anot of Exdride. ano product of Expropyl androstan l7B-ol-3,ll ample I. ample I. dione. XXXIV 5;3cyano prodpropionic anhy- 17-propionate of 5fi- XXI 17a-vinyl-testosterone- 5a and fifi-isomers of the S-cyano not of Exdride. cyano product of and 5-carbarnyl analogs of 17aample V. Example V. vinyl endrostan 17 3 ol 3,11- 10 XXXV EQ-carbamyl benzoio anhy- 17-lbenzoate of 5adione. product of dride. carbamyl product XXII..- 17a iso propen(-l)y 5a and Bfi-isorners of the 5-cyano Example VI. of Example VI.

progesterone. and fi-carbamyl analogs of 17a- XXXVL... fifl-carhamyl cyclopentyl-pro- 2l-cyclopentylprd iso propenyl pregnan 3,20 product of picnic anhypioante of 5B-oar dione. Example X. dride. hamyl-pregnan- XXIII IYa-alkyl-testosterone. 5a and BB-isomers of the E-cyano 115,21-diol-3,20-

and 5-carbamyl analogs of 17adione. alkyl androstan 17B ol 3,11- XXXVII 5fl-cyano prodbutyric anhy- 17-Ebutyrate of 5- dione. not of Exdride. cyano testan-17fi- XXIV- 17a pentenyl-proges- 5a and B S-isomers of the 5-cyano ample V. ol-3-0ne.

tcrone. and S-oarbamyl analogs of 17a- XXXVIIL- 5fi-cyan0 prodcaproic anhy- 17-capr0ate of 5- pentenyl -pregnan 3,20 dione. not of Exdride. cyano tcstan-UB- XXV 17a ethinycorticoster- 5a and fifl-isomers of the fi-cyano ample I. ol-3-one.

one. and S-carbamyl analogs of 17a- XXXIX--- 5fl oyano prodcyclopentyl-pro- 17-oyclopentylproethinyl prcgnan- 11,8,2l-diol-3, not of Expionio anhypionate of 5 cyano 20-dione. 20 ample I. dride. testan-l75-ol-3-one. XXVI..-" 17a propin(-l)yl tes- 5a and fifi'isomers of the 5-cyano tosterone and S-carbarnyl analogs of 17aprojpinyl androstan 17fl-ol-3,

1- ione.

EXAMPLE XL 2 5 Alternatively, the dlhydroxyacetone side chain was regenerated by heating a S-cyano or 5-carbamyl-17,20 EXAMPLE XXVII 20,21-bis-methylenedioxy-pregnane with 50% acetic acid A mixture of 5 g. of 5oz-cyano-17,20;20,2l-bls-methylfor 7 hours at 100 C.; the product was precipitated by ene-droxy-pregnan-l 1,8-01-3-one, the BMD compo nd diluting with water and then acetylated at C-21 by the produced 1n the preceding Example XVII and 100 cc. of hod of Example XXXI. There was thus prep 60% formic acid was stirred on a steam bath for 1 hour and cooled; the precipitate was collected by filtration, washed with water, dried and recrystallized from acetonehexane. There was thus obtained Sa-cyano pregnan- 11p,17a,21 triol 3,20 -dione, namely 50: cyano 4,5-

' dihydro-hydrocortisone.

Following the procedure of Example XXVH, the final products listed in Table 11 below can be obtained from the indicated starting materials:

EXAMPLE A mixture of 1 g. of 5ct-cyano-pregnan-115,17a-21- triol-3,20-dione, obtained as described in Example XX, 5 cc. of acetic anhydride and 10 cc. of pyridine Was kept overnight at room temperature and then poured into water, heated for 1 hour on a steam bath and cooled; the precipitate was collected, washed with water, dried and recrystallized from acetone-hexane, thus producing 5acyano-pregnan-11,8,17a,21-triol-3,20-dione 2l-acetate.

EXAMPLE XXXII By following the procedure of Example XXXI, there was prepared SB-carbamyl-dihydrotestosterone l7-propionate by reaction of the free compound with propionic anhydride.

Following the procedure of Example XPQQI, the final products listed in Table .111 below. can be obtained from the starting compounds indicated.

for example, 5ot-cyano-4,5-dihydro-cortisone 2lacetate.

We claim:

'1. A process for preparing S-cyano and S-carbamyl analogs of certain 4,5 dihydro derivatives of steroidal A -3-ketohormones, comprising the steps of reacting a starting compound having the general formula:

wherein A is a radical arrangement selected from the group consisting of H lower aliphatic radical lower aliphatic radical acyloxy,

CO-OH5 CO-OHzOH CH-GH2 bis-methylenedioxy, and

(JO-CHaOH OH g and =0 with the. cyanide of a metal selected from the group consisting of the alkali-metals and the alkaline earth metals, in the presence of a hydroxy'lated organic solvent,

so as to produce a new mixture of analogs being of the to five hours with potassium cyanide in mixture with a I solvent which is a lower fatty alcohol.

3. The process according to claim 1, characterized in that the cyanide is sodium cyanide.

4. The process as described in claim. 1, characterized in that the starting compound is 17,20;20,2l-bis-methylenedioxy-A -pregnen-3-one, and further comprising the step of heating the resulting compounds in aqueous organic acid in order to regenerate the dihydroacetone side chain of the aforesaid starting compound;

5. The process as described in claim 1, further comprising the step of reacting a resulting analog with the anhydride of a carboXylic acid having up to 12 carbon atoms, so as to produce the corresponding ester of the analog having the primary and secondary hydroxyl groups thereof esterified.

6. A compound of the following formula:

wherein R is, selected from the group consisting of hydrogen and methyl; R is selected from the group consisting of cyano and carbamyl; R is selected from the group consisting of hydrogen and a hydrocarbon carboxylic acyl group of less than 12 carbon atoms; Y is selected from the group consisting of hydrogen, B-hydroXyl, oc-hYdIOXYl and keto and X is selected from the group consisting of hydrogen and fluorine.

7. A compound of the following formula:

H wherein R is selected from the group consisting of hy- 8. A compound of the following formula:

wherein R is selected from the group consisting of hydrogen and methyl; R is selected from the group consisting of cyano and carbamyl; Y is selected from the group consisting of hydrogen, B-hydroxyl, a-hydroxyl and keto; X is selected from the group consisting of hydrogen and fluorine and R is selected from the group consisting of hydrogen, hydroxy and hydrocarbon carboxylic acyloxy I of less than 12 carbon atoms.

9. A compound of the following formula:

wherein R is selected from the group consisting of hydrogen and methyl; R is selected from the group consisting of cyano and carbamyl; R is selected from the group consisting of hydrogen and a hydrocarbon carboxylic acyl group of less than 12 carbon atoms; Y is sel'ected from the group consisting of hydrogen, S-hydroxyl, a-hydroxyl and keto and X is selected from the group consisting of hydrogen and fluorine.

10. A compound of the following formula:

OH OR wherein R is selected from the group consisting of hydrogen and methyl; R is selected from the group consisting of cyano and carbamyl; and R is selected from the group R1 wherein R is selected from the group consisting of hydrogen and methyl; R is selected from the group consisting of cyano and carbamyl; X is selected from the group consisting of hydrogen and fluorine and Y is selected from the group consisting of hydrogen, p-hydroxyl, oc-hydroxyl and keto.

13. 5-cyano-dihydrotestosterone.

14. 5fl-carbamyl-dihydrotestosterone-l7-propionate.

15. 5a-cyano-4,5-dihydro-cortisone-Zl-acetate.

-16. 5a-cyano-4,5-dihydro-hydrocortisone-21-acetate.

17. The hydrocarbon carboxylic acid esters of less than 12 carbon atoms of S-cyano-l7a-hydroxy-pregnane-3,20- dione.

18. The hydrocarbon canboxylic acid esters of less than 12 carbon atoms of S-carbamyl-17a-hydroxy-pregnane- 3,20-dione.

1 9. S-cyano-pregnane-17u,21-diol-3,20 dione.

20. S-carbamyl-pregnane-17u,21-dio1-3,20-dione.

No references cited. 

1. A PROCESS FOR PREPARING 5-CYANO AND 5-CARBAMYL ANALOGS OF CERTAIN 4,5 DIHYDRO DERIVATIVES OF STEROIDAL $4-3-KETO-HORMONES, COMPRISING THE STEPS OF REACTING A STARTING COMPOUND HAVING THE GENERAL FORMULA:
 12. A COMPOUND OF THE FOLLOWING FORMULA: 